THE METABOLIC DISORDER OF ALZHEIMER’S DISEASE IN THE 5XFAD MOUSE MODEL AND HOW INSULIN AND GHRELIN CAN BE USED AS THERAPEUTICS

Abstract

A subset of patients with Alzheimer’s disease exhibit involuntary age-related weight loss not related to failure to eat. This weight loss can reduce the quality of life, increase frailty, and mortality. The 5xFAD mouse model of AD also exhibits this phenotype. Consequently, we evaluated the metabolic factors underlying age-related weight loss in the 5xFAD mouse model. Male and female 5xFAD mice tested in metabolic cages (Experiment 1) at 12 months of age showed metabolic abnormalities compared to WT mice (B6SJLF2/J) that were sex specific. Both male and female 5xFAD mice exhibited weight loss, fat loss, and lean mass loss, and in males this was driven by a hypermetabolic system. However, in females this weight loss was driven by a hypometabolic system that impaired activity, feeding behaviour, and fat production. To attenuate this loss in weight and body fat we injected the 5xFAD mice with the orexigenic hormone ghrelin (Experiment 2). Ghrelin attenuated weight loss and increased food intake in all mice with the exception of male 5xFAD mice. Ghrelin also improved spatial memory in all mice except the 5xFAD males. An increase in fat storage did not occur after ghrelin injections. Rather, ghrelin administration reduced WAT amounts. Along with metabolic impairments in the body, both AD patients and 5xFAD mice exhibit metabolic impairments in the brain such as reduced glucose metabolism. We therefore infused insulin intransally as a means to enhance insulin signalling via enhancing the activation of the PI3K-Akt pathway (Experiment 3). Insulin infusions increased Akt activation, improved spatial memory, muscle strength, and reduced frailty without inducing hypoglycemia. Both insulin and ghrelin injections reduced freezing behaviour in the 5xFAD mice suggesting that these hormones may have anxiolytic properties. The results of these studies indicate that the 5xFAD mice exhibit metabolic impairments in the brain and body and the nature of this metabolic impairment is dependent on sex. While ghrelin administration attenuated weight loss it did not increase adiposity suggesting that a different route of injection, e.g. intranasal, or drug, e.g. corticosteroids, may be an effective way to induce fat storage. Intra-nasal insulin enhanced the activation of the PI3K-Akt pathway thereby improving spatial memory and reducing frailty. These studies support the hypothesis that AD is a metabolic disorder of the brain and body and indicate that the symptoms of this disorder may be partially reversed by hormones such as insulin and ghrelin that enhance Akt signalling and prevent weight loss.